tbuckley/cabot-search huggingface dataset:
NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).
Authors: Zev A. Wainberg, Davide Melisi, Teresa Macarulla, Roberto Pazo-Cid, Sreenivasa R Chandana, Christelle De La Fouchardiere, Andrew Peter Dean, Igor Kiss, Woojin Lee, Thorsten Oliver Goetze, Eric Van Cutsem, Andrew Scott Paulson, Tanios S. Bekaii-Saab, Shubham Pant, Richard Hubner, Zhimin Xiao, Huanyu Chen, Fawzi Benzaghou, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2023)

LBA661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m 2 + 5-FU 2400 mg/m 2 + LV 400 mg/m 2 + oxaliplatin 60 mg/m 2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m 2 + gemcitabine 1000 mg/m 2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235 .[Table: see text]
Effect of Tabernero's prognostic subgroups or development of neutropenia on survival outcomes of patients with refractory metastatic colorectal cancer (mCRC) treated with trifluridine/tipiracil plus bevacizumab (TASBEV) in real-world practice.
Authors: Nieves P. Martinez-Lago, Beatriz Alonso de Castro, Cristina Reboredo Rendo, Teresa Calleja, Martín Igor Gómez-Randulfe Rodríguez, Sofia Silva Diaz, Iria Parajó Vázquez, Maria Mateos Salvador, Fernando Busto Fernandez, Begona Grana Suarez, Juan De la camara, Margarita Reboredo Lopez
Journal: Journal of Clinical Oncology (2023)

99 Background: TASBEV, compared with TAS-102, was associated with an improvement in progression-free survival (PFS) with tolerable toxicity in a randomized, open-label phase 2 trial. However, the subgroups of patients who may benefit from long-term TASBEV treatment are unknown. Methods: We conducted a retrospective, observational study of patients (pts) with mCRC refractory or intolerant to standard therapies treated with TAS-102 30-35 mg/m2 twice daily on days 1–5 and 8–12 every 28 days plus BEV 5 mg/kg on days 1 and 15 at University Hospital a Coruña (Spain). Results: We recorded 47 pts treated between July 2019 to June 2022. Median age was 65 years (range 41 – 82 years), 78.7% ECOG PS0-1, 51.1% RASmt, 78.7% of pts had liver and 23.4%, peritoneal metastases; 29.8% time since diagnosis of 1st metastases &lt;18 months and 57.4% poor prognostic Tabernero Subgroup. Previous treatment included 94.3% previous antiVEGF treatment and 74.5% received TAS-102 BEV as 3rd line of treatment. Median of cycles received was 4 (range 1-15 cycles). ORR and DCR were 2.4% and 48.8%, respectively. With a median follow up of 15.7 months, median PFS was 4.3 months (95% CI, 3.4-5.1 months) and median OS was 9.8 months (95% CI, 7.3-12.3 months). Univariate analysis of prognostic factors for progression-free and overall survival are listed in the table. Conclusions: In our series identified that Tabernero's prognostic subgroups or the development of grade 3-4 neutropenia during treatment, among others; identify patients who may benefit from long-term TASBEV treatment. [Table: see text]
Effectiveness and safety of encorafenib-cetuximab in BRAF<sup>V600E</sup> metastatic colorectal cancer: Confidence study.
Authors: Ana Fernandez Montes, Javier Ros, Begoña Graña, Pilar García-Alfonso, Elena Brozos, Marcos Melian, Ana M. Jiménez-Gordo, Eva Martinez de Castro, Isabel Busquier, Javier Gallego, Cristina Gravalos, Marta Covela, Ana Ruiz-Casado, Encarnación González Flores, Mariajose Safont, Juana Maria Cano, Carmen Alonso Lopez, Maria Jose Gomez-Reina, Olga Donnay, Enrique Aranda
Journal: Journal of Clinical Oncology (2023)

126 Background: BRAF V600E mutant metastatic colorectal cancer (mCRC) has a poor prognosis. The BEACON trial demonstrated an improvement in tumor response, overall survival (OS), and progression-free survival (PFS) when administering encorafenib-cetuximab (EC) to patients (pts) who progressed after 1 or 2 therapy lines. This study provides a retrospective analysis of the effectiveness and safety of EC in the real-world setting in Spain. Methods: This retrospective analysis included BRAF V600E mCRC pts treated with EC in 2 nd line treatment, recruited from March to July 2022. The Co-primary study endpoints included effectiveness based on PFS and OS. Secondary endpoints included sociodemographic and clinical characteristics of patients before EC initiation, overall response rate (ORR), and safety. Results: From March to July 2022, 81 evaluable pts were included. Sociodemographic and clinical characteristics are displayed.A median (interquartile range [IQR]) of 6.0 (4.0-13.0) cycles of encorafenib and 6.0 (4.0-14.5) cycles of cetuximab were administered. Median treatment duration was 4.4 (2.6-7.8) months (m) and 4.4 m (2.8-7.6) respectively. The ORR and disease control rate was 33.8 % (CI 95% 23.4-45.5) and 68.8 (CI 95% 57.3 – 78.9) respectively. One (1.2%) pt achieved complete response At data cut-offwith a 9.7 median follow-up, 50 (61.7%) pts had died, all of them due to disease progression. Median (95% Confidence Interval, CI) OS was 12.6 m (8.0-17.3) and median PFS was 5.0 m (3.8-6.2). The 12-m OS and 12-m PFS rates were 54.6% (95% CI, 43.3-65.9) and 19.9% (10.5-29.3) respectively. Pts with neutrophils/lymphocyte ratio (NLR) ≥3 had worse OS (HR, 1.8 95% CI 1.0-3.2; p &lt; 0.049) and worse PFS (HR, 2.3, 1.4-3.8; p &lt; 0.002). Disease progression (86.7%) was the most frequent cause of treatment discontinuation, followed by unacceptable AEs (3.7%). Eleven pts (13.5%) experienced treatment-related graded 3 or 4 AEs, mainly acne (3.7%). Treatment-related deaths were not reported. Conclusions: This study provides real-world data of BRAF V600E mCRC pts treated with EC combination in routine clinical practice in Spain. EC effectiveness and safety were consistent with the results obtained in clinical trials. [Table: see text]
An open-label, multi-center phase IIIb study of durvalumab and tremelimumab as first-line treatment in patients with unresectable hepatocellular carcinoma (TREMENDOUS study).
Authors: Jia Fan, Shukui Qin, Hui-Chuan Sun
Journal: Journal of Clinical Oncology (2023)

TPS628 Background: Hepatocellular carcinoma (HCC) is of high incidence and mortality rate in China, with nearly half of them are diagnosed as advanced or metastatic stage at the initial diagnosis. First-line treatment options for patients with advanced disease previously included tyrosine kinase inhibitors and immune checkpoint inhibitors in combination with vascular endothelial growth factor. Recently, the phase III HIMALAYA trial investigated the STRIDE regimen, tremelimumab 300mg × 1 dose and durvalumab 1500mg every 4 weeks, compared to sorafenib in previously untreated locally advanced or metastatic HCC patients, and resulted in significantly improved overall survival (OS) (16.4 mos vs 13.8mos, HR=0.78) and a well-tolerated safety profile (≥grade 3 treatment-related adverse events 25.8% vs 36.9% ). Notably, the HIMALAYA trial did not enroll subject from mainland China and excluded patients with class Child-Pugh B liver dysfunction or ECOG performance status (PS) 2. We hypothesize the STRIDE regimen will be safe and well tolerated in Chinese patients with locally advanced or metastatic HCC with Child-Pugh class A or B liver dysfunction or ECOG PS 0-2. In addition, the study will also assess efficacy and explore biomarkers. Methods: This will be an open label, multi-center phase IIIb study investigating the safety and efficacy of the STRIDE regimen in Chinese unresectable HCC patients without prior systemic therapy. Patients with Child-Pugh A liver dysfunction and ECOG PS 0-1 will be enrolled in cohort 1, while patients with Child-Pugh B liver dysfunction or ECOG PS 2 will be enrolled in cohort 2. Patients with main portal vein tumor thrombosis (Vp4), clinically significant ascites or hepatic encephalopathy, or active or prior documented gastrointestinal bleeding within 12 months will be excluded. We plan to enroll 300 patients with the primary endpoint of grade 3-5 adverse event (AE) rate by CTCAE v5.0 and adverse events of special interest (AESI). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), progression free survival (PFS), OS, OS rate at 6 months and 12 months. Patients of both cohorts will receive a single dose of tremelimumab 300 mg and durvalumab 1500 mg at Cycle 1 (Week 0), followed by durvalumab 1500 mg monotherapy every 4 weeks until confirmed disease progression or unacceptable toxicity. Archival or fresh tumor biopsy will be required at baseline. The trial is currently screening eligible subjects. Clinical trial information: CTR20222433 .
Feasibility of establishing and drug screening patient-derived rectal organoid models from pretreatment rectal cancer biopsies.
Authors: Scarlett Acklin-Wehnert, Divya Dayanidhi, Brian G. Czito, Manisha Palta, Christopher Willett, Christine Elissa Eyler, Christopher Mantyh, John Migaly, Julie Thacker, Billy Lan, David S. Hsu
Journal: Journal of Clinical Oncology (2023)

176 Background: Response to neoadjuvant chemotherapy and radiation therapy in the treatment of locally advanced rectal cancer is heterogenous and prognostic of clinical outcomes, necessitating the need for predictive biomarkers to guide personalized treatment recommendations. Sensitivity to a given chemotherapy in patient-derived organoids predicts patient response to that chemotherapy, establishing it as a promising model for efforts to ascertain predictive biomarkers and personalize treatment decisions. This study assessed the feasibility of obtaining patient-derived rectal organoids from standard of care pre-treatment proctoscopy biopsies. Methods: In this clinical trial (NCT04371198), biopsies were obtained from patients with stage II rectal adenocarcinoma prior to receipt of neoadjuvant therapy. Tissue samples were mechanically and enzymatically dissociated to obtain a single cell suspension. Cells were then mixed with matrigel at a ratio of 2,000 cells:5 µL Matrigel in a 50ul dome and plated on a 24 well tissue culture plate with colorectal cancer organoid media at 37 o C/5% CO 2 . Established patient-derived organoids were then used to perform drug screens with clinically-applicable chemotherapeutics including oxaliplatin, irinotecan and 5-FU, followed by high throughput drug screen using our recently published MicroOrganoSpheres platform using the NCI Approved Oncology Drugs Set VI* library. Results: Of the 20 patients enrolled, 17 (85%) patient-derived organoids were created from pre-treatment specimens. 15 (88%) of these samples were successfully established as defined by the ability to passage organoids for at least two passages. All established samples were used to perform standard of care drug screens and high throughout drug screens, which demonstrated differences in drug sensitivities among the samples. Moreover, within two weeks of receiving the sample, four established quickly enough to complete drug screening with oxaliplatin, SN38, and 5-Fluorouracil. Conclusions: These results demonstrate the feasibility of establishing patient-derived rectal organoids from biopsy specimens obtained by proctoscopy, and reinforce the utility of patient-derived organoids as a tractable ex vivo platform to personalize rectal cancer treatment. Planned future directions include in vitro determination of radiation therapy sensitivity as well as systematic assessment of the correlation between individual patients and their organoid model. Clinical trial information: NCT04371198 .
Significance of alterations in DNA damage repair (DDR) genes in advanced biliary cancers (ABCs) treated with second-line active-symptom-control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+FOLFOX) in the randomised phase III, multicentre, open-label ABC-06 trial.
Authors: Angela Lamarca, Daniel H. Palmer, Harpreet Singh Wasan, Paul J. Ross, Yuk Ting Ma, Arvind Arora, Stephen Falk, Roopinder Gillmore, Jonathan Wadsley, Kinnari Patel, Alan Anthoney, Anthony Maraveyas, Claire Hobbs, Lorna Wilkinson, Timothy Macdonald, Claire Hartley, David Ryder, John A. Bridgewater, Juan W. Valle
Journal: Journal of Clinical Oncology (2023)

593 Background: The ABC-06 clinical trial established ASC+mFOLFOX as the standard of care treatment after Cisplatin and Gemcitabine (CisGem) for ABC. Translational research explored the role of alterations in DDR-related genes in the context of the ABC-06 clinical trial. Methods: Translational research using samples collected from the ABC-06 trial included all recruited patients with tissue sample containing &gt;20% tumour cellularity with sufficient DNA extracted for analysis. Primary objective: assess the prevalence of somatic mutations within DDR genes in ABC. Secondary objectives: explore the impact of somatic mutations in DDR genes on: A) Patient’s response to platinum-based chemotherapy (predictive biomarker): 1) Retrospectively, using progression-free survival (PFS) data from 1 st -line chemotherapy and 2) Prospectively, by assessing the impact on PFS/radiological response to 2 nd -line FOLFOX (vs. control) and B) Overall survival (prognostic biomarker). Survival analysis was performed with Kaplan-Meier and Cox Regression. Results: Of 162 pts randomised, 83 had a sample available for analysis; of these, analysis failed in 24 despite &gt;20% tumour content. Thus, a total of 59 patients (30 ASC arm, 29 ASC+FOLFOX arm) were eligible for this translational analysis: male 50.85%, metastatic 77.97%, intrahepatic cholangiocarcinoma 47.46%, adenocarcinoma 91.53%, median age 65.84 years (95% CI 63.36-68.91). Pathogenic mutations in DDR genes were identified in 22 patients (37.29%). PFS did not vary depending on the DDR-gene alterations either in the first-line setting with CisGem (n=59; 8.73 months vs 8.18 months; p-value 0.155) or with second-line FOLFOX (n=29; 3.19 months vs 3.45 months; p-value 0.098). Median OS for DDR-altered patients was 4.59 months (95% CI 2.17-5.88) (vs 7.23 months (95% CI 5.45-8.28) for DDR-wild-type); HR 2.63 (95% CI 1.48-4.67); p-value 0.001. This prognostic impact was confirmed when the prognostic model was adjusted for treatment arm and stratification factors (HR 3.75 (95% CI 1.99-7.09); p-value &lt;0.001). Conclusions: For ABC patients, the presence of DDR-related gene pathogenic mutations are present in around one third of patients. Despite presence of DDR-mutations having a negative prognostic impact, their predictive role is not confirmed either for first-line CisGem or second-line FOLFOX. Clinical trial information: NCT01926236 .
PERSIST: A multicenter, randomized phase II trial of perioperative oxaliplatin and S-1 (SOX) with or without sintilimab in resectable locally advanced gastric/gastroesophageal junction cancer (GC/GEJC).
Authors: Xuewei Ding, Xuejun Wang, Bin Li, Longgang Wang, Honghai Guo, Liang Shang, Wenbai Huang, Liangliang Wu, Bin Ke, Yong Liu, Ning Liu, Baogui Wang, Mingzhi Cai, Jingyu Deng, Rupeng Zhang, Jiancheng Zhang, Jie Chai, Qun Zhao, Leping Li, Han Liang
Journal: Journal of Clinical Oncology (2023)

364 Background: RESOLVE study shows clinically meaningful improvement in perioperative SOX in patients with locally advanced GC/GEJC undergoing D2 gastrectomy. Addition of PD-1 inhibitor to chemotherapy shows significant clinical benefit in first-line treatment of advanced GC/GEJC. This trial was designed to compare the perioperative sintilimab combined with SOX versus perioperative SOX in patients with resectable locally advanced GC/GEJC. Methods: PERSIST is a multicenter, prospective, open-label, randomized-controlled phase II study. Patients with histologically or cytologically confirmed GC/GEJC, clinical stage II-III, no previous systemic treatment, ECOG performance status (PS) of 0 or 1 were eligible for inclusion. Patients will be randomized (1:1) to received either perioperative sintilimab (200 mg d1 Q3W, three cycles preoperatively and up to 1 year postoperatively) in combined with SOX (oxaliplatin 130 mg/m² d1, oral S-1 40–60 mg BID d1-14 Q3W, three cycles preoperatively and five cycles postoperatively) in experimental group or perioperative SOX alone in control group. The primary endpoint was the pCR rate. The secondary endpoints were the MPR rate, down-staging rate, 3-years DFS rate, 5-years OS rate, safety. The study is registered with Clinicaltrials.gov: NCT04982939. Results: As of September 2022, 101 patients were enrolled, with median age 61 years (range 31-75 years), males 85 (84.2%), cT2/3/4/X 2(2.0%)/5(5.0%)/93(92.1%)/1(1.0%), cN0/1/2/3/X 10(10.0%)/42(41.6%)/27(26.7%)/9(8.9%)/13(12.9%), and GC/GEJC 92(91.1%)/9(8.9%). Forty-seven patients (experimental group:26, control group:21) underwent radical resection and all achieved R0 resection. The pCR rates in the experimental group and control group were 26.9% (95%CI 11.6%-47.8%) and 4.8% (95%CI 0.1%-23.8%), respectively. The MPR rates in the experimental group and control group were 69.2% (95%CI 48.2%-85.7%) and 28.6% (95%CI 11.3%-52.2%), respectively. 76.9% (20/26) and 52.4% (11/21) patients achieved down-staging in the experimental group and control group. Three patients developed grade 3–4 surgical complications. Grade 3–4 TRAEs included thrombocytopenia (4.0%), anemia (3.0%), neutropenia (2.0%), allergic reaction (2.0%), pneumonia (1.0%), myocardial infarction (1.0%). The median postoperative hospital stay in the experimental and control group were 10 days (range 7-38 days) and 11 days (range 7-66 days). Conclusions: Compared to SOX chemotherapy alone, sintilimab combined with SOX resulted in an encouraging pCR rate, MPR rate and downstaging rate as perioperative treatment for resectable locally advanced GC/GEJC, and safety was manageable. Clinical trial information: NCT04982939 .
Survival results by the prospectively determined clinical staging for locally advanced gastric cancer: An ancillary study of JCOG1302A (JCOG1302A2).
Authors: Tsutomu Hayashi, Junki Mizusawa, Tadayoshi Hashimoto, Takeo Fukagawa, Rie Makuuchi, Makoto Hikage, Kazunari Misawa, Takanobu Yamada, Takashi Nomura, Yasuyuki Kawachi, Takahiro Kinoshita, Ryohei Kawabata, Hiroshi Yabusaki, Takeshi Sano, Mitsuru Sasako, Takaki Yoshikawa, Narikazu Boku, Masanori Terashima
Journal: Journal of Clinical Oncology (2023)

392 Background: Recently, neoadjuvant chemotherapy has been recognized as a promising strategy to improve the survival of patients with advanced gastric cancer. On the other hand, given the adverse events and treatment cost of chemotherapy, the candidate for NAC should be limited to patients who can benefit from NAC. In fact, as previously reported, the proportion of pathological stage I tumors was 50.4% in cT2N0, 38.7% in cT2N(+), 26.7% in cT3N0, 10.6% in cT3N(+), 9.0% in cT4aN0, and 3.0% in cT4aN(+). Therefore, clinical staging before initiation of treatment is increasingly important for determining therapeutic strategy. However, the long-term survival stratified by the prospectively-determined clinical stage has not been fully investigated. Methods: Between July 2013 and November 2014, the JCOG1302A examined 1260 patients with a clinical diagnosis of cT2/T3/T4, cN0/N1/N2/N3, M0, except for diffuse large tumors like linitis plastica and extensive bulky nodal diseases according to the Japanese Classification of Gastric Carcinoma (3rd English edition). The cT diagnosis was made by upper gastrointestinal endoscopy and comprehensive findings on upper abdominal contrast CT scan with 1 or 5 mm slice thickness. Lymph nodes with a shortest dimension greater than 8 mm or a longest dimension greater than 10 mm were defined as positive for metastasis. In this follow-up study, the survival data by stratifying the clinical staging were evaluated. Results: Among 1260 patients, survival data of 1177 were analyzed. With a median follow-up for 821 surviving patients of 6.0 years, the 5y-OS was 82.1% (95% CI, 77.3-85.9) in cT2 (n=319), 72.7% (68.2-76.6) in cT3 (n=450), 60.0% (54.9-64.7) in cT4a (n=401), and 40.0% (5.2-75.3) in cT4b (n=6), while that was 78.0% (74.2-81.2) in cN0 (n=560), 70.6% (65.4-75.2) in cN1 (n=350), 59.1% (52.5-65.1) in cN2 (n=241), and 28.4% (12.7-46.5) in cN3 (n=26), respectively. When combined with cT and cN, 5y-OS was 83.5% (77.8-87.8) in cT2N0 (n=226), 77.2% (71.0-82.2) in cT3N0 (n=232), 66.8% (56.3-75.2) in cT4aN0 (n=100), 100% in cT4bN0 (n=1), 78.7% (68.6-85.8) in cT2N(+)(n=93), 68.0% (61.1-73.8) in cT3N(+)(n=218), 57.7% (51.7-63.2) in cT4aN(+)(n=301), and 25.0% (0.9-66.5) in cT4bN(+)(n=5). Conclusions: Both the survival and the proportion of overdiagnosis of stage I patients in patients with cT4aN0, categorized as cstage IIB, was almost same as in those cT3N(+) categorized as cstage III. In considering the candidate for further treatment development of NAC with high toxic regime in future, cT3N(+) and cT4aN0 should be considered as equivalent category.